Tetrahedron 62 (2006) 10615–10622

Singlet oxygen addition to chiral allylic alcohols and subsequentperoxyacetalization with b-naphthaldehyde: synthesis of

diastereomerically pure 3-b-naphthyl-substituted 1,2,4-trioxanes

Axel G. Griesbeck,* Tamer T. El-Idreesy and Johann Lex

Institute of Organic Chemistry, University of Cologne, Greinstr. 4, D-50939 K€oln/Cologne, Germany

Received 15 February 2006; revised 18 May 2006; accepted 18 May 2006

Available online 7 September 2006

Abstract—The synthesis of a series of eight b-naphthyl-substituted 1,2,4-trioxanes 3a–h by a sequence of singlet oxygen ene reaction ofallylic alcohols 1a–h and Lewis acid catalyzed peroxyacetalization of the allylic hydroperoxides 2a–h with b-naphthaldehyde is reported.The ene reactions were performed by solid-state photooxygenation in dye-crosslinked polystyrene beads and resulted in mixtures of diaste-reoisomeric hydroperoxides 2. Boron trifluoride catalyzed peroxyacetalization resulted in the formation of 3, as well as the 1,2,4-trioxanes 4and 5, which were formed via acid catalyzed b-hydroperoxy alcohol cleavage.� 2006 Elsevier Ltd. All rights reserved.

1. Introduction

1.1. Singlet oxygen chemistry

In 1948, Schenck was the first to describe the singlet oxygenene reaction1 (therefore often termed Schenck reaction).2 Inthe course of this reaction, 1O2 attacks one center of a CCdouble bond with abstraction of an allylic hydrogen atomor an allylic silyl group (from a silyl enolether in case ofthe silyl–ene reaction) with simultaneous allylic shift of thedouble bond. As a result of this reaction, allylic hydroper-oxides or O-silylated a-hydroperoxy carbonyl compoundsare formed (Scheme 1). Since the first report, the 1O2 ene re-action has attracted major interest not only in the mechanisticphotochemistry but also in modern organic synthesis. Severalmechanisms have been postulated for this reaction withconcerted or ‘concerted two-stage’ mechanisms,3 as well as1,4-biradicals,4 1,4-zwitterions,5 perepoxide, dioxetane6 orexciplex intermediates.

O2

H

H

O OHOO1O2

Scheme 1. Singlet oxygen ene reaction.

Keywords: Ene reaction; Singlet oxygen; 1,2,4-Trioxanes; Peroxyacetaliza-tion; Catalysis.* Corresponding author. E-mail: griesbeck@uni-koeln.de

0040–4020/$ - see front matter � 2006 Elsevier Ltd. All rights reserved.doi:10.1016/j.tet.2006.05.093

The results of Stephenson’s elegant inter- and intramolecularisotope effect experiment7 with isotopically labeled tetra-methylethylenes provided evidence for the perepoxide inter-mediate. Also, the small negative activation enthalpies andhighly negative activation entropies observed for the singletoxygen ene reaction from kinetic measurements have shownthat the reaction of 1O2 with electron-rich olefins proceed103 times slower than the diffusion rate, which accountsfor the presence of non-productive encounters between 1O2

and the alkene favoring the participation of a reversiblyformed exciplex as intermediate.8 As a result, a three-stepmechanism involving exciplex and perepoxide can beassumed for the ene reaction.

The regiochemistry of the ene reaction with substrates withmultiple sites for allylic hydrogen transfer was extensivelystudied and several general effects can predict the regio-selective introduction of the hydroperoxy group: (a) thecis-effect9 (syn-effect): in the reaction of 1O2 with trisubsti-tuted alkenes10 or enol ethers,11 the allylic hydrogen atomson the more substituted side of the double bond are morereactive for H-abstraction by 1O2; (b) the gem-effect12 thatleads to highly selective abstraction of an allylic hydrogenatom from a substituent in a position of an a,b-unsaturatedcarbonyl compound; (c) the large-group effect13 that leads toselective (moderate) abstraction of an allylic hydrogen fromthe substituent geminal to a large group.

Several factors that control the p-facial selectivity of singletoxygen ene reaction are known and can be summarized asfollows: (a) steric factors: in view of the small size of the

10616 A. G. Griesbeck et al. / Tetrahedron 62 (2006) 10615–10622

reactive molecule singlet oxygen, steric interactions are ex-pected to be less important in directing the facial approach.However, in rigid (cyclic and polycyclic) substrates wherechanges in conformation that minimize steric factors are re-stricted, this effect is more pronounced and steric shielding ofone face of the double bond may bias 1O2 attack to occurpredominantly on the other face of the p-system;14 (b) con-formational effects: for an efficient hydrogen abstraction tooccur, the reactive allylic hydrogen atoms must adopt a con-formation, which places them perpendicular to the alkeneplane.15 This factor is often highly effective in rigid com-pounds in which allylic hydrogen atoms can be conforma-tionally fixed in an optimal transfer geometry on one faceof the double bond; (c) electronic effects and hydrogen bond-ing: the simplest tetrasubstituted alkene, 2,3-dimethyl-2-butene with a highly nucleophilic double bond reacts morethan 30 times faster than the corresponding trisubstitutedalkene, 2-methyl-2-butene, and the latter reacts about 15times faster than the disubstituted alkene Z-2-butene. Adamand Br€unker elegantly used hydrogen bonding interactionsbetween the substrate and the incoming singlet oxygen forcontrol of the diastereoselectivity in the photooxygenationof allylic alcohols and other substrates.16 The coordinationof singlet oxygen to the hydroxy group in the more stableconformer (not destabilized by 1,3-allylic strain) directs theapproach of the electrophilic 1O2 to one face of the doublebond (Scheme 2).

R

OH

H

O

R

HOO

RH

OH

OO

1O2 1O2

R

OH

OOHR

OH

OOHsyn-7anti-7

major productminor product

Scheme 2. Mechanism of the singlet oxygen ene reaction with chiral allylicalcohols.

We have recently demonstrated that the use of polymersupport as reaction media with non-covalently adsorbed orcovalently linked porphyrin dyes are convenient processesfor the solvent-free photooxygenation of unsaturated organicsubstrates.17 Especially the use of chiral allylic alcohols isinformative in that the diastereoselectivity is a tool foranalyzing the reaction environment and supramoleculareffects.18 We have used this concept for the synthesis ofb-hydroperoxy alcohols, which we have applied as sub-strates for the synthesis of a series of 1,2,4-trioxanes in thecontext of a study on antimalarial peroxides.

1.2. Artemisinin and antimalarial peroxides

One of the major drawbacks of artemisinin is its poor solubil-ity in both water and oil.19 To overcome this problem artemi-sinin is reduced to dihydroartemisinin, which leads to thepreparation of a series of semisynthetic first-generationartemisinin analogues, including artemether, arteether, andartesunate, which are used broadly in many areas of the worldwhere malaria is endemic (Fig. 1).20 Venugopalan et al. syn-thesized various ethers and thioethers of dihydroartemisinin

by treatment with alkyl, aryl, alkynyl, and heteroalkyl alco-hols or thiols in the presence of boron trifluoride. The prod-ucts were tested in vivo and some show antimalarialactivity comparable to arteether.21

The moderate bioavailability and rapid clearance (short phar-macological half-life) observed with these artemisinin-derived drugs are the major disadvantages. This often resultsfrom the poor chemical and metabolic stability of the addi-tional acetal functional group present in such derivatives.To overcome this problem, many C-10-carba analoguesand C-10-aryl analogues of dihydroartemisinin that are meta-bolically more robust were synthesized. Of relevance are theC-10-alkyl and the C-10-aryl or heteroaromatic derivativesprepared by Haynes,22 Posner,23 O’Neill,24 Jung,25 andZiffer.26 The development of the artemisinin combinationtherapy concept was recently achieved by the synthesis ofeffective drugs that simultaneously contain the 1,2,4-tri-oxane moiety covalently bound with another active antima-larial pharmacophore, such as aminoquinolines27 or aliphaticdiamines.28 The high activity of these molecules, termed tri-oxaquines, is rationalized by the combination of a peroxidicentity that is a fast and potential alkylating agent, in the samemolecule with the aminoquinoline unit, which is character-ized by easy penetration of the infected erythrocytes.29

The goal of the present work is to show that aromatic sidegroups can be easily incorporated into 1,2,4-trioxanes thatare produced by a sequence of 1O2 ene reaction with chiralallylic alcohols and subsequent peroxyacetalization. As amodel compound for aromatic and heteroaromatic carbonylcompounds, b-naphthaldehyde was applied.

2. Results and discussion

The photooxygenation of a series of allylic alcohols 1a–husing PS–DVB polymer matrix doped with adsorbed por-phyrin sensitizers resulted in the formation of a syn (orthreo) and anti (or erythro) diastereomeric mixture of thevic-hydroperoxy alcohols in good yields (Scheme 3). Theb-hydroperoxy alcohols are stable at rt and can be kept inthe refrigerator for weeks without decomposition.

R

OH

OOHR

OH

OOHsyn-2a-h anti-2a-h

+3O2/TPPPS-DVBR

OH

1a-h

Scheme 3. Solvent-free photooxygenation of the allylic alcohols 1a–h usingTPP embedded in PS–DVB matrix.

OO

OO

H

H

OR

OO

OO

H

H

OHR = Me (artemether)R = Et (arteether)R = COCH2CH2COO-

(artesunate)

Dihydroartemisinin

Figure 1. Artemisinin-derivatives with improved pharmacological proper-ties.

10617A. G. Griesbeck et al. / Tetrahedron 62 (2006) 10615–10622

The diastereoselectivity of the ene reaction using the com-mercial PS–DVB that were modified with adsorbed porphy-rin sensitizer (Table 1) showed similar values to thatobtained with the polymer-bound sensitizer systems, TSP–S–DVB or PP–S–DVB (TSP¼tetrastyrylporphyrin; PP¼protoporphyrin IX),30 but lower than for solution phase(e.g., tetrachloromethane), accounting for an intermolecularhydrogen bonding between the concentrated substrate mole-cules in both polymer systems. Comparison of the chemicalyields and the diastereoselectivities in the solvent-freephotooxygenation reaction of the allylic alcohols 1a–h isshown in Table 1.

The photooxygenation of the allylic alcohol 1h (possessingtwo stereogenic centers, applied as a 1:1 diastereoisomericmixture) afforded four diastereomers of the b-hydroxy allylichydroperoxides, two correspond to the major products withreaction-induced syn configuration (assigned as syn,syn-2hand syn,anti-2h) and two to the minor compounds with reac-tion-induced anti configuration (assigned as anti,syn-2h andanti,anti-2h). The photooxygenation of 1h is depicted inScheme 4. The diastereomeric ratio of the individual pairsof major and minor isomers is about 1:1. The major diastereo-mers constitute about 85% of the product mixture (deter-mined from 13C NMR).

OH

OOH

OH

OOH

OH

OOH

OH

OOH

3O2/TPPPS-DVB

syn,syn-1h syn,anti-1h

anti,anti-1hanti,syn-1h

OH

1h

Scheme 4. Solvent-free photooxygenation of the allylic alcohol 1h.

The peroxyacetalization reaction of 2-naphthaldehyde withthe b-hydroperoxy alcohols proceeded under standard reac-tion conditions31 with boron trifluoride as Lewis acid catalystand resulted in the 1,2,4-trioxanes 3a–h in moderate yields(Table 2). The carbonyl component was applied in slightexcess and thus, appreciable amounts of the BF3-catalyzedcleavage and cross-peroxyacetalization products wereisolated in each case. This is shown for the reaction of thecyclohexyl-substituted b-hydroperoxy alcohol 2f (Scheme 5)

Table 1. Photooxygenation of the allylic alcohols 1a–h using solvent-freeapproach with PS–DVB copolymer

Compound R d.r.a syn:anti Yield (%)

2a Et 77:23 722b n-Pr 79:21 782c n-Bu 79:21 782d i-Bu 80:20 772e c-Pr 62:38 802f c-Hex 88:12 652g CH2CH]CH2 75:25 692h CH(Me)CH]CH2

b 63

a The diastereoselectivity was determined from the integration of the char-acteristic signals in the NMR of the crude reaction mixture.

b Four diastereomers were obtained in a ratio of 39:39:11:11.

with b-naphthaldehyde. The hydroperoxy alcohol 2f isreacted with 1.1 equiv of the aldehyde in CH2Cl2 in the pres-ence of a catalytic amount of BF3 to form the 1,2,4-trioxane3f in 41% yield in addition to the cross-peroxyacetalizationproducts 4f and 5f in 22 and 16% yields, respectively. Inmost cases, these side-products were not isolated and charac-terized solely from the NMR spectra (not reported in Section4). It is, however, possible to obtain these compounds (also1,2,4-trioxane structures) in good yields by BF3-catalyzedoxidative cleavage and cross-peroxyacetalization of thehydroperoxides in the absence of an additional carbonylcomponent. The assignment of the structure of 3f is basedon 1H as well as 13C NMR spectra, IR, elemental, andHRMS analyses. The IR spectrum shows the characteristicC–O stretching at 1112, 1074 cm�1 and O–O at 906,822 cm�1. The 1H NMR shows the characteristic singlet at6.38 ppm corresponding to the peroxyacetal proton (H-3)and the doublet at 4.87 ppm related to the peroxy proton(H-6) due to coupling with H-5 (3JHH¼9.5 Hz) indicatingtrans configuration. Surprisingly, H-5 appears also as doublet(and not doublet of doublet as expected); this can be ascribedto a dihedral angle of roughly 90� between this proton and theCH proton of the cyclohexyl group. The 2-naphthyl group islocated also in equatorial position as confirmed by X-ray forthe two analogous examples 3a and 3b (Fig. 2 and Table 3).In no case were the products from the minor diastereoiso-meric allylic hydroperoxides (anti isomers) isolated fromthe crude reaction mixtures (where they appear with about5–10% relative yields).

OH

OOHO O

OH

O

BF3.Et2O / CH2Cl22f 3f41%

O O

O

O O

O+ +

4f 5f

C-3C-5

C-6

Scheme 5. Lewis acid catalyzed peroxyacetalization of the b-hydroperoxyalcohol 2f with b-naphthaldehyde.

3. Conclusion

In summary, the singlet oxygen ene reaction with chiralallylic alcohols 1 in polystyrene matrices proceeds with ex-cellent yields and gives the allylic hydroperoxides 2 withgood (syn) diastereoselectivities. Subsequent Lewis acidcatalyzed peroxyacetalization with b-naphthaldehyde results

Table 2. Peroxyacetalization of the allylic hydroperoxides 2a–h withb-naphthaldehyde

Compound R Yielda (%)

3a Et 243b n-Pr 403c n-Bu 433d i-Bu 213e c-Pr 313f c-Hex 413g CH2CH]CH2 143h CH(Me)CH]CH2 15

a Yields after purification of the crude materials.

10618 A. G. Griesbeck et al. / Tetrahedron 62 (2006) 10615–10622

in the formation of diastereomerically pure (all-equatorial)3-naphthyl-1,2,4-trioxanes 3 in moderate yields besides thecross-peroxyacetalization products 4 and 5.

4. Experimental

4.1. General procedures (GP)

4.1.1. GP 1. Solvent-free type-II photooxygenation reac-tion in polymer matrices.

4.1.1.1. Using commercial PS–DVB copolymer. Thepolymer beads (ca. 2–3 g, Fluka, polystyrene copolymerwith 1% divinylbenzene) were introduced into a Petri dish(19 cm diameter) and were pretreated with CH2Cl2(20 mL) and the excess solvent evaporated by a vacuumline. The substrate (ca. 10 mmol) and the non-polar sensi-tizer (tetraphenylporphyrin, TPP, or tetratolylporphyrin,TTP, ca. 3–6 mg) in ethyl acetate (20 mL) were subse-quently added and the excess solvent evaporated by leaving

Figure 2. Structure of 1,2,4-trioxanes 3a and 3b in the crystal.

Table 3. Crystal structure analyses data for 1,2,4-trioxanes 3a and 3b

Crystal data 3a 3b

Empirical formula C18H20O3 C19H22O3

Formula weight 284.34 298.37Temperature [K] 100(2) 100(2)Crystal system Monoclinic MonoclinicSpace group P21/c C2/ca [A] 13.614(2) 34.338(1)b [A] 5.6245(5) 5.362(1)c [A] 19.903(3) 20.740(1)a [�] 90 90b [�] 97.456(4) 121.32(1)g [�] 90 90Volume [A3] 1511.1(4) 3262.2(6)Z 4 8dcalcd [g cm�3] 1.250 1.215Crystal size [mm] 0.1�0.1�0.3 0.35�0.25�0.25No. refl. collected 6492 10220No. unique refl. 3146 3554No. obsd refl. 1251 2305R1 0.0663 0.0427wR2 0.1452 0.0900Largest diff. peak/

hole [e/A�3]0.428/�0.215 0.232/�0.166

the Petri dish in a well ventilated hood. The Petri dish is cov-ered with a glass plate and the sandy solid is irradiated withhalogen lamp or sodium street lamp. The polymer beadswere subsequently washed with ethanol (3�30 mL) andfiltered (the beads can be used again for at least six cycleswithout pre-swelling). The solvent was evaporated underreduced pressure (CAUTION: water bath temperature shouldnot exceed 30 �C.) and the composition of the product wasdetermined by 1H as well as 13C NMR and the crude prod-ucts applied directly for peroxyacetalization.

4.1.1.2. Using synthetic TSP–S–DVB or PP–S–DVBcopolymers.30 The dye-cross-linked polymer beads(TSP–S–DVB or PP–S–DVB, ca. 0.60 g) in a Petri dish(14 cm in diameter) were swollen by CH2Cl2 (20 mL),then the substrate (ca. 5 mmol) in ethyl acetate (20 mL)was added. Subsequent treatment as in Section 4.1.1.1affords the product.

4.1.2. GP 2. General procedure for the peroxyacetaliza-tion reaction and 1,2,4-trioxanes synthesis. To a stirredsolution of b-hydroxy hydroperoxides and the carbonylreagent in dry CH2Cl2 (100 mL) was added at rt a catalyticamount of boron trifluoride etherate (ca. 0.2 mL) and themixture was further stirred for about 12 h (overnight) atthe same temperature. Volatile carbonyl compounds wereused in 5–10-fold molar excess, less volatile carbonyl com-pounds were used in 1.2–1.5-fold molar excess. The reactionmixture was then partitioned between CH2Cl2 and saturatedNaHCO3 solution and the phases were separated. The aque-ous phase was extracted with CH2Cl2 (3�30 mL) and thecombined organic phases were washed with brine, water,and dried over Na2SO4. Solvent evaporation (CAUTION:water bath temperature should not exceed 30 �C.) followedby chromatographic purification afforded the 1,2,4-trioxaneas pure product.

4.1.2.1. 4-Hydroperoxy-5-methylhex-5-en-3-ol (2a).Photooxygenation of 5-methylhex-4-en-3-ol (1a) (1.0 g,8.77 mmol) for 48 h according to GP 1 afforded a diastereo-meric mixture (d.r. syn:anti, 77:23) of b-hydroxy allylichydroperoxides 2a (0.92 g, 6.30 mmol, 72%) as colorless oil.

syn-2a: 1H NMR: d 0.92 (t, 3H, J¼7.5 Hz, CH3CH2), 1.23–1.58 (m, 2H, CH2CH3), 1.68 (m, 3H, CH3C]), 3.55 (ddd,1H, J¼5.9, 5.9, 8.5 Hz, CH–OH), 4.15 (d, 1H, J¼8.5 Hz,CH–OOH), 5.01 (m, 2H, CH2]C). 13C NMR: d 9.6 (q,CH3CH2), 17.8 (q, CH3C]), 25.5 (t, CH2CH3), 71.8(d, CH–OH), 93.4 (d, CH–OOH), 116.5 (t, CH2]C), 141.4(s, C]CH2).

anti-2a: 1H NMR additional significant signals: d 0.93(t, 3H, J¼7.4 Hz, CH3CH2), 1.76 (s, 3H, CH3C]), 3.69(m, 1H, CH–OH), 4.30 (d, 1H, J¼4.7 Hz, CH–OOH), 5.04(m, 2H, CH2]C). 13C NMR: d 10.3 (q, CH3CH2), 19.3(q, CH3C]), 25.0 (t, CH2CH3), 72.2 (d, CH–OH), 91.4(d, CH–OOH), 115.3 (t, CH2]C), 141.2 (s, C]CH2).

4.1.2.2. 3-Hydroperoxy-2-methylhept-1-en-4-ol (2b).Photooxygenation of 2-methylhept-2-en-4-ol (1b) (1.0 g,7.81 mmol) for 48 h according to GP 1 afforded a diastereo-meric mixture (d.r. syn:anti, 79:21) of b-hydroxy allylichydroperoxides 2b (0.98 g, 6.13 mmol, 78%) as colorless oil.

10619A. G. Griesbeck et al. / Tetrahedron 62 (2006) 10615–10622

syn-2b: 1H NMR: d 0.87 (t, 3H, J¼7.1 Hz, CH3CH2), 1.20–1.58 (m, 4H, CH2CH2), 1.68 (m, 3H, CH3C]), 3.63(m, 1H, CH–OH), 4.13 (d, 1H, J¼8.5 Hz, CH–OOH), 5.01(m, 2H, CH2]C). 13C NMR: d 13.8 (q, CH3CH2), 17.8(t, CH2CH3), 18.3 (q, CH3C]), 34.6 (t, CH2CH2), 70.3(d, CH–OH), 93.8 (d, CH–OOH), 116.6 (t, CH2]C), 141.4(s, C]CH2).

anti-2b: 1H NMR additional significant signals: d 0.87 (t,3H, J¼7.1 Hz, CH3CH2), 1.76 (m, 3H, CH3C]), 3.78 (m,1H, CH–OH), 4.29 (d, 1H, J¼4.4 Hz, CH–OOH). 13CNMR: d¼13.9 (q, CH3CH2), 19.0 (t, CH2CH3), 19.4 (q,CH3C]), 34.0 (t, CH2CH2), 70.5 (d, CH–OH), 91.6 (d,CH–OOH), 115.2 (t, CH2]C), 141.2 (s, C]CH2).

4.1.2.3. 3-Hydroperoxy-2-methyloct-1-en-4-ol (2c).Photooxygenation of 2-methyloct-2-en-4-ol (1c) (1.19 g,8.38 mmol) for 60 h according to GP 1 afforded a diastereo-meric mixture (d.r. syn:anti, 79:21) of b-hydroxy allylichydroperoxides 2c (1.14 g, 6.55 mmol, 78%) as faint yellowoil.

syn-2c: 1H NMR: d 0.85 (t, 3H, J¼7.1 Hz, CH3CH2), 1.21–1.57 (m, 6H, CH2CH2CH2), 1.70 (s, 3H, CH3C]), 3.64 (m,1H, CH–OH), 4.15 (d, 1H, J¼8.4 Hz, CH–OOH), 5.03 (m,2H, CH2]C). 13C NMR: d 13.9 (q, CH3CH2), 17.9 (q,CH3C]), 22.5 (t, CH2CH3), 27.3 (t, CH2CH2), 32.2(t, CH2CH2), 70.6 (d, CH–OH), 93.7 (d, CH–OOH), 116.6(t, CH2]C), 141.3 (s, C]CH2).

anti-2c: 1H NMR additional significant signals: d 1.77 (s,3H, CH3C]), 3.75 (m, 1H, CH–OH), 4.30 (d, 1H, J¼4.7 Hz, CH–OOH). 13C NMR: d 13.9 (q, CH3CH2), 19.3(q, CH3C]), 22.5 (t, CH2CH3), 28.0 (t, CH2CH2), 32.2(t, CH2CH2), 70.7 (d, CH–OH), 91.7 (d, CH–OOH), 116.6(t, CH2]C), 141.2 (s, C]CH2).

4.1.2.4. 3-Hydroperoxy-2,6-dimethylhept-1-en-4-ol(2d). Photooxygenation of 2,6-dimethylhept-2-en-4-ol (1d)(1.25 g, 8.80 mmol) for 60 h according to GP 1 affordeda diastereomeric mixture (d.r. syn:anti, 80:20) of b-hydroxyallylic hydroperoxides 2d (1.18 g, 6.78 mmol, 77%) ascolorless oil.

syn-2d: 1H NMR: d 0.83 (d, 3H, J¼6.5 Hz, CH3CH), 0.87 (d,3H, J¼6.8 Hz, CH3CH), 1.03 (m, 1H, CH2CH), 1.32 (m, 1H,CH2CH), 1.68 (s, 3H, CH3C]), 1.81 (m, 1H, CHCH2), 3.68(m, 1H, CH–OH), 4.09 (d, 1H, J¼8.4 Hz, CH–OOH), 5.0(m, 2H, CH2]C). 13C NMR: d 17.9 (q, CH3CH), 21.1 (q,CH3C]), 23.8 (d, CHCH2), 24.0 (q, CH3CH), 41.6(t, CH2CH), 68.7 (d, CH–OH), 94.2 (d, CH–OOH), 116.6(t, CH2]C), 141.4 (s, C]CH2).

anti-2d: 1H NMR additional significant signals: d 0.84 (d,3H, J¼6.7 Hz, CH3CH), 1.76 (s, 3H, CH3C]), 3.83(m, 1H, CH–OH), 4.26 (d, 1H, J¼4.5 Hz, CH–OOH), 5.05(m, 2H, CH2]C). 13C NMR: d 19.4 (q, CH3CH), 21.4(q, CH3C]), 23.6 (d, CHCH2), 24.7 (q, CH3CH), 41.1(t, CH2CH), 68.9 (d, CH–OH), 92.0 (d, CH–OOH), 115.2(t, CH2]C), 141.3 (s, C]CH2).

4.1.2.5. 1-Cyclopropyl-2-hydroperoxy-3-methylbut-3-en-1-ol (2e). Photooxygenation of 1-cyclopropyl-3-

methylbut-2-en-1-ol (1e) (1.0 g, 7.94 mmol) for 60 haccording to GP 1 afforded a diastereomeric mixture (d.r.syn:anti, 62:38) of b-hydroxy allylic hydroperoxides 2e(1.0 g, 6.33 mmol, 80%) as colorless oil.

syn-2e: 1H NMR: d 0.20–0.52 (m, 4H, CH2CH2), 0.78–0.99(m, 1H, CH), 1.75 (m, 3H, CH3C]), 3.07 (dd, 1H, J¼7.9,7.9 Hz, CH–OH), 4.29 (d, 1H, J¼9.3 Hz, CH–OOH), 5.05(m, 2H, CH2]C). 13C NMR: d 1.8 (t, CH2CH2), 3.2(t, CH2CH2), 14.0 (d, CH), 18.9 (q, CH3C]), 75.0(d, CH–OH), 93.3 (d, CH–OOH), 115.5 (t, CH2]C),141.6 (s, C]CH2).

anti-2e: 1H NMR additional significant signals: d 1.82 (m,3H, CH3C]), 3.14 (dd, 1H, J¼4.3, 8.8 Hz, CH–OH), 4.41(d, 1H, J¼4.3 Hz, CH–OOH). 13C NMR: d 2.6 (t, CH2CH2),2.9 (t, CH2CH2), 13.3 (d, CH), 19.6 (q, CH3C]), 75.6(d, CH–OH), 91.2 (d, CH–OOH), 115.4 (t, CH2]C), 141.3(s, C]CH2).

4.1.2.6. 1-Cyclohexyl-2-hydroperoxy-3-methylbut-3-en-1-ol (2f). Photooxygenation of 1-cyclohexyl-3-methyl-but-2-en-1-ol (1f) (1.30 g, 7.74 mmol) for 60 h accordingto GP 1 afforded a diastereomeric mixture (d.r. syn:anti,88:12) of b-hydroxy allylic hydroperoxides 2f (1.0 g,5.0 mmol, 65%) as faint yellow oil.

syn-2f: 1H NMR: d 0.83–1.90 (m, 11H, CH and CH2), 1.64 (s,3H, CH3C]), 3.43 (m, 1H, CH–OH), 4.24 (d, 1H, J¼8.5 Hz,CH–OOH), 4.97 (s, 2H, CH2]C). 13C NMR: d 17.7 (q,CH3C]), 25.3 (t, CH2), 25.9 (t, CH2), 26.1 (t, CH2), 26.4(t, CH2), 30.3, 30.5 (t, CH2), 39.1 (d, CH), 74.3 (d,CH–OH), 91.0 (d, CH–OOH), 115.9 (t, CH2]C), 141.6(s, C]CH2).

anti-2f: 1H NMR additional significant signals: d 4.29 (d, 1H,J¼6.0 Hz, CH–OOH). 13C NMR additional significant sig-nals: d 39.3 (d, CH), 89.2 (d, CH–OOH), 112.9 (t, CH2]C).

4.1.2.7. 3-Hydroperoxy-2-methylhepta-1,6-dien-4-ol(2g). Photooxygenation of 6-methylhepta-1,5-dien-4-ol(1g) (1.16 g, 9.21 mmol) for 60 h according to GP 1 affordeda diastereomeric mixture (d.r. syn:anti, 75:25) of b-hydroxyallylic hydroperoxides 2g (1.0 g, 6.33 mmol, 69%) as faintyellow oil.

syn-2g: 1H NMR: d 1.70 (m, 3H, CH3C]), 2.02–2.37 (m,2H, CH2), 3.71 (ddd, 1H, J¼3.7, 8.3, 8.3 Hz, CH–OH),4.17 (d, 1H, J¼8.4 Hz, CH–OOH), 5.05 (m, 4H, CH2]Cand CH2]CH), 5.79 (m, 1H, CH]CH2). 13C NMR:d 17.9 (q, CH3C]), 37.1 (t, CH2), 70.0 (d, CH–OH), 92.8(d, CH–OOH), 116.8 (t, CH2]CH), 118.1 (t, CH2]C),133.8 (d, CH]CH2), 141.1 (s, C]CH2).

anti-2g: 1H NMR additional significant signals: d 1.76(m, 3H, CH3C]), 3.82 (m, 1H, CH–OH), 4.31 (d, 1H,J¼4.9 Hz, CH–OOH). 13C NMR: d 19.1 (q, CH3C]),36.6 (t, CH2), 69.9 (d, CH–OH), 91.0 (d, CH–OOH), 115.6(t, CH2]CH), 117.9 (t, CH2]C), 134.5 (d, CH]CH2),141.0 (s, C]CH2).

4.1.2.8. 3-Hydroperoxy-2,5-dimethylhepta-1,6-dien-4-ol (2h). Photooxygenation of 3,6-dimethylhepta-1,5-dien-4-ol

10620 A. G. Griesbeck et al. / Tetrahedron 62 (2006) 10615–10622

(1h) (1.20 g, 8.57 mmol) for 60 h according to GP 1 affordedan oil composed of the inseparable diastereomeric mix-ture (0.92 g, 5.35 mmol, 63%) composed of syn,syn-2h,syn,anti-2h (d.r. 1:1) as major product and a diastereomericmixture of anti,syn-2h and anti,anti-2h (d.r. 1:1) as minorproducts (major/minor: 78:22 ratio).

syn,syn-2h: 1H NMR: d 0.90 (d, 3H, J¼6.9 Hz, CH3CH),1.63 (s, 3H, CH3C]), 2.17 (m, 1H, CHCH3), 3.50 (m, 1H,CH–OH), 4.12 (d, 1H, J¼8.8 Hz, CH–OOH), 4.94 (m, 4H,CH2]C and CH2]CH), 5.74 (m, 1H, CH]CH2). 13CNMR: d 12.1 (q, CH3CH), 17.8 (q, CH3C]), 38.7 (d,CHCH3), 73.1 (d, CH–OH), 90.8 (d, CH–OOH), 114.3 (t,CH2]CH), 116.2 (t, CH2]C), 141.1 (s, C]CH2), 141.2(d, CH]CH2).

syn,anti-2h: 1H NMR additional significant signals: d 0.99(d, 3H, J¼5.4 Hz, CH3CH), 3.52 (m, 1H, CH–OH), 4.22(d, 1H, J¼8.0 Hz, CH–OOH). 13C NMR: d 17.6 (q,CH3C]), 39.0 (d, CHCH3), 73.4 (d, CH–OH), 91.3 (d,CH–OOH), 116.2 (t, CH2]CH), 116.8 (t, CH2]C), 137.8(d, CH]CH2), 140.6 (s, C]CH2).

anti,syn-2h: 13C NMR significant signals: d 72.5 (d, CH–OH), 89.2 (d, CH–OOH).

anti,anti-2h: 13C NMR significant signals: d 72.5 (d, CH–OH), 89.5 (d, CH–OOH).

4.1.2.9. (3RS,5RS,6RS)-5-Ethyl-3-(naphthalen-2-yl)-6-(prop-1-en-2-yl)-1,2,4-trioxane (3a). Following GP 2,a solution of 4-hydroperoxy-5-methylhex-5-en-3-ol (2a)(1.22 g, 8.36 mmol) and b-naphthaldehyde (1.30 g,8.33 mmol) in CH2Cl2 was treated with a catalytic amountof BF3$Et2O (0.2 mL). Usual work-up and further puri-fication of the crude product by preparative thick-layerchromatography (SiO2, EA/n-hex, 1:10, Rf¼0.71) affordsthe 1,2,4-trioxane (0.57 g, 2.0 mmol, 24%) as viscous oil,which crystallizes into white solid on standing, mp 73–75 �C. 1H NMR: d 1.14 (dd, 3H, J¼7.4, 7.4 Hz, CH3CH2),1.70 (m, 2H, CH2CH3), 1.86 (m, 3H, CH3C]), 3.96 (ddd,1H, J¼3.8, 7.9, 9.3 Hz, OCH), 4.67 (d, 1H, J¼9.3 Hz,OOCH), 5.18 (m, 1H, CH2]), 5.23 (s, 1H, CH2]), 6.43(s, 1H, OCHOO), 7.48–8.07 (m, 7H, Harom); 13C NMR:d 9.4 (q, CH3CH2), 19.9 (q, CH3C]), 23.6 (t, CH2CH3),78.5 (d, OCH), 87.4 (d, OOCH), 104.0 (d, OCHOO), 118.4(t, CH2]C), 124.0 (d, CHarom), 126.1 (d, CHarom), 126.6 (d,CHarom), 126.8 (d, CHarom), 127.6 (d, CHarom), 128.0(d, CHarom), 128.3 (d, CHarom), 131.9 (s, Cqarom), 132.8 (s,Cqarom), 133.9 (s, Cqarom), 138.7 (s, C]CH2); IR: (CsI) n(cm�1)¼3064, 2980, 2925, 2898, 1664, 1605, 1071, 908,824; MS: (EI, 70 eV) m/z (%)¼284 (M+, 4), 156 (C11H8O+,100), 155 (C11H7O+, 95), 128 (C10H8

+, 22), 127 (C10H7+,

73), 96 (C7H12+ , 47), 81 (C6H9

+, 17); HRMS: (EI, 70 eV,C18H20O3) calcd: M¼284.141 g/mol, found: M¼284.141�0.005 g/mol; CH-analysis: (C18H20O3, M¼284.35 g/mol)calcd: C, 76.03; H, 7.09, found: C, 75.53; H, 7.11.

4.1.2.10. (3RS,5RS,6RS)-3-(Naphthalen-2-yl)-6-(prop-1-en-2-yl)-5-propyl-1,2,4-trioxane (3b). Following GP 2,a solution of 3-hydroperoxy-2-methylhept-1-en-4-ol (2b)(1.20 g, 7.50 mmol) and b-naphthaldehyde (1.18 g,7.56 mmol) in CH2Cl2 was treated with a catalytic amount

of BF3$Et2O (0.2 mL). Usual work-up and further purifica-tion of the crude product by preparative thick-layer chroma-tography (SiO2, EA/n-hex, 1:10, Rf¼0.66) afforded the pure1,2,4-trioxane (0.89 g, 2.99 mmol, 40%) as colorless oil,which crystallizes on standing, mp 78–80 �C. 1H NMR:d 1.02 (t, 3H, J¼7.1 Hz, CH3CH2), 1.47–1.79 (m, 4H,CH2CH2), 1.86 (m, 3H, CH3C]), 4.04 (ddd, 1H, J¼3.1,8.1, 9.3 Hz, OCH), 4.67 (d, 1H, J¼9.3 Hz, OOCH), 5.19(m, 1H, CH2]), 5.24 (s, 1H, CH2]), 6.43 (s, 1H, OCHOO),7.47–8.07 (m, 7H, Harom); 13C NMR: d 13.9 (q, CH3CH2),18.1 (t, CH2CH3), 19.7 (q, CH3C]), 32.5 (t, CH2CH2),77.1 (d, OCH), 87.7 (d, OOCH), 104.0 (d, OCHOO), 118.5(t, CH2]), 124.0 (d, CHarom), 126.1 (d, CHarom), 126.6 (d,CHarom), 126.7 (d, CHarom), 127.6 (d, CHarom), 128.0 (d,CHarom), 128.3 (d, CHarom), 131.9 (s, Cqarom), 132.8 (s,Cqarom), 133.9 (s, Cqarom), 138.7 (s, C]CH2); IR: (CsI) n(cm�1)¼2957, 2934, 1664, 1605, 1576, 1362, 1340, 1092,1075, 907; MS: (EI, 70 eV) m/z (%)¼298 (M+, 3), 226(M+�C4H8O, 2), 156 (C11H8O+, 92), 155 (C11H7O+, 100),128 (C10H8

+, 22), 127 (C10H7+, 77), 110 (C8H14

+ , 27), 95(C7H11

+ , 8); HRMS: (EI, 70 eV, C19H22O3) calcd:M¼298.157 g/mol, found: M¼298.157�0.005 g/mol; CH-analysis: (C19H22O3, M¼298.39) calcd: C, 76.48; H, 7.43,found: C, 76.25; H, 7.27.

4.1.2.11. (3RS,5RS,6RS)-5-Butyl-3-(naphthalen-2-yl)-6-(prop-1-en-2-yl)-1,2,4-trioxane (3c). Following GP 2,a solution of 3-hydroperoxy-2-methyloct-1-en-4-ol (2c)(1.24 g, 7.13 mmol) and b-naphthaldehyde (1.11 g,7.12 mmol) in CH2Cl2 was treated with a catalytic amountof BF3$Et2O (0.2 mL). Usual work-up and further purifica-tion of the crude product by preparative thick-layer chroma-tography (SiO2, EA/n-hex, 1:10, Rf¼0.85) afforded the pure1,2,4-trioxane (0.96 g, 3.08 mmol, 43%) as viscous oil,which crystallizes on standing, mp 51–53 �C. 1H NMR:d 0.96 (t, 3H, J¼7.2 Hz, CH3CH2), 1.25–1.70 (m, 6H,CH2), 1.85 (s, 3H, CH3C]), 4.01 (m, 1H, OCH), 4.64 (d,1H, J¼9.3 Hz, OOCH), 5.18 (m, 1H, CH2]), 5.22 (s, 1H,CH2]), 6.41 (s, 1H, OCHOO), 7.49–8.05 (m, 7H, Harom);13C NMR: d 13.9 (q, CH3CH2), 19.7 (q, CH3C]), 22.6(t, CH2CH3), 27.0 (t, CH2CH2), 30.1 (t, CH2CH2), 77.4(d, OCH), 87.7 (d, OOCH), 104.1 (d, OCHOO), 118.5(t, CH2]C), 124.1 (d, CHarom), 126.1 (d, CHarom), 126.6(d, CHarom), 126.8 (d, CHarom), 127.6 (d, CHarom), 128.1 (d,CHarom), 128.4 (d, CHarom), 132.0 (s, Cqarom), 132.8(s, Cqarom), 133.9 (s, Cqarom), 138.8 (s, C]CH2); MS: (EI,70 eV) m/z (%)¼312 (M+, 1), 226 (M+�C5H10O, less than1), 156 (C11H8O+, 100), 155 (C11H7O+, 93), 127 (C10H7

+,72), 124 (C9H16

+ , 38); HRMS: (EI, 70 eV, C20H24O3) calcd:M¼312.173 g/mol, found: M¼312.173�0.005 g/mol; CH-analysis: (C20H24O3, M¼312.40) calcd: C, 76.89; H, 7.74,found: C, 76.61; H, 7.78.

4.1.2.12. (3RS,5RS,6RS)-5-Isobutyl-3-(naphthalen-2-yl)-6-(prop-1-en-2-yl)-1,2,4-trioxane (3d). Following GP2, a solution of 3-hydroperoxy-2,6-dimethylhept-1-en-4-ol(2d) (1.21 g, 6.95 mmol) and b-naphthaldehyde (1.09 g,6.99 mmol) in CH2Cl2 was treated with a catalytic amountof BF3$Et2O (0.2 mL). Usual work-up and further puri-fication of the crude product by preparative thick-layerchromatography (SiO2, EA/n-hex, 1:10, Rf¼0.71) affordsthe 1,2,4-trioxane (0.46 g, 1.47 mmol, 21%) as an oil, whichcrystallizes on standing to white solid, mp 60–62 �C.

10621A. G. Griesbeck et al. / Tetrahedron 62 (2006) 10615–10622

1H NMR: d 1.01 (d, 3H, J¼6.6 Hz, CH3CH), 1.04 (d, 3H, J¼6.8 Hz, CH3CH), 1.33 (m, 1H, CH2CH), 1.70 (m, 1H,CH2CH), 1.87 (s, 3H, CH3C]), 2.08 (m, 1H, CHCH2), 4.12(ddd, 1H, J¼2.3, 9.1, 10.3 Hz, OCH), 4.65 (d, 1H,J¼9.1 Hz, OOCH), 5.19 (m, 1H, CH2]), 5.24 (m, 1H,CH2]), 6.45 (s, 1H, OCHOO), 7.49–8.07 (m, 5H, Harom);13C NMR: d 19.6 (q, CH3C]), 21.5 (q, CH3CH), 23.6(d, CHCH2), 23.7 (q, CH3CH), 39.2 (t, CH2CH), 75.6(d, OCH), 88.0 (d, OOCH), 104.0 (d, OCHOO), 118.7 (t,CH2]), 124.0 (d, CHarom), 126.1 (d, CHarom), 126.6(d, CHarom), 126.7 (d, CHarom), 127.6 (d, CHarom), 128.0(d, CHarom), 128.3 (d, CHarom), 131.9 (s, Cqarom), 132.8 (s,Cqarom), 133.9 (s, Cqarom), 138.6 (s, C]CH2); IR: (CsI) n(cm�1)¼3095, 2956, 2934, 1605, 1347, 1098, 1080, 997,863, 817; MS: (EI, 70 eV) m/z (%)¼312 (M+, 3), 226(M+�C5H10O, 2), 156 (C11H8O+, 100), 155 (C11H7O+,97), 128 (C10H8

+, 30), 127 (C10H7+, 70), 124 (C9H16

+ , 27),109 (C8H13

+ , 17); HRMS: (EI, 70 eV, C20H24O3) calcd:M¼312.173 g/mol, found: M¼312.173�0.005 g/mol; CH-analysis: (C20H24O3, M¼312.40 g/mol) calcd: C, 76.89; H,7.74, found: C, 76.61; H, 7.63.

4.1.2.13. (3RS,5RS,6RS)-5-Cyclopropyl-3-(naphthalen-2-yl)-6-(prop-1-en-2-yl)-1,2,4-trioxane (3e). FollowingGP 2, a solution of 1-cyclopropyl-2-hydroperoxy-3-methyl-but-3-en-1-ol (2e) (1.25 g, 7.91 mmol) and b-naphthalde-hyde (1.23 g, 7.88 mmol) in CH2Cl2 was treated with acatalytic amount of BF3$Et2O (0.2 mL). Usual work-upand further purification of the crude product by preparativethick-layer chromatography (SiO2, EA/n-hex, 1:10, Rf¼0.67) affords the pure 1,2,4-trioxane as yellow oil, whichcrystallizes upon standing (0.72 g, 2.43 mmol, 31%). 1HNMR: d 0.39–0.64 (m, 4H, CH2CH2), 0.98 (m, 1H,CH(CH2)2), 1.87 (m, 3H, CH3C]), 3.44 (dd, 1H, J¼7.4,9.1 Hz, OCH), 4.68 (d, 1H, J¼9.12 Hz, OOCH), 5.14 (m,2H, CH2]), 6.31 (s, 1H, OCHOO), 7.46–7.98 (m, 7H,Harom); 13C NMR: d 2.0 (t, CH2), 2.8 (t, CH2), 11.6(d, CH(CH2)2), 20.7 (q, CH3C]), 81.0 (d, OCH), 87.8 (d,OOCH), 104.0 (d, OCHOO), 117.5 (t, CH2]), 124.2 (d,CHarom), 126.2 (d, CHarom), 126.7 (d, CHarom), 127.0(d, CHarom), 127.7 (d, CHarom), 128.2 (d, CHarom), 128.5(d, CHarom), 131.8 (s, Cqarom), 132.9 (s, Cqarom), 134.1 (s,Cqarom), 139.9 (s, C]CH2); IR: (Film) n (cm�1)¼3088,3011, 2968, 2934, 1647, 1603, 1126, 1071, 904, 859, 814;HRMS: (EI, 70 eV, C19H20O3) calcd: M¼296.141 g/mol,found: M¼296.141�0.005 g/mol; CH-analysis: (C19H20O3,M¼296.36) calcd: C, 77.00; H, 6.80, found: C, 76.47; H,6.83.

4.1.2.14. (3RS,5RS,6RS)-5-Cyclohexyl-3-(naphthalen-2-yl)-6-(prop-1-en-2-yl)-1,2,4-trioxane (3f). FollowingGP 2, a solution of 1-cyclohexyl-2-hydroperoxy-3-methyl-but-3-en-1-ol (2f) (1.20 g, 6.0 mmol) and b-naphthaldehyde(0.94 g, 6.03 mmol) in CH2Cl2 was treated with a catalyticamount of BF3$Et2O (0.2 mL). Usual work-up and furtherpurification of the crude product by preparative thick-layerchromatography (SiO2, EA/n-hex, 1:10, Rf¼0.65) affordedthe pure 1,2,4-trioxanes (0.83 mg, 2.46 mmol, 41%) as whitesolid, mp 88–90 �C. Additionally, the cross-peroxyacetaliza-tion products 4f and 5, were isolated in 22 and 16% yields,respectively (by NMR from the crude reaction mixture). 1HNMR: d 1.06–1.94 (m, 11H, CH and CH2), 1.85 (s, 3H,CH3C]), 3.87 (d, 1H, J¼9.5 Hz, OCH), 4.87 (d, 1H,

J¼9.5 Hz, OOCH), 5.18 (m, 2H, CH2]), 6.38 (s, 1H,OCHOO), 7.47–8.02 (m, 7H, Harom); 13C NMR: d 19.7 (q,CH3C]), 26.2 (t, CH2), 26.2 (t, CH2), 26.3 (t, CH2), 26.5(t, CH2), 30.1 (t, CH2), 38.4 (d, CH), 81.4 (d, OCH), 85.2(d, OOCH), 104.1 (d, OCHOO), 118.5 (t, CH2]C), 124.1(d, CHarom), 126.1 (d, CHarom), 126.6 (d, CHarom), 126.9 (d,CHarom), 127.6 (d, CHarom), 128.0 (d, CHarom), 128.4 (d,CHarom), 132.1 (s, Cqarom), 132.8 (s, Cqarom), 133.9 (s,Cqarom), 138.9 (s, C]CH2); IR: (CsI) n (cm�1)¼2933,2856, 1653, 1647, 1605, 1560, 1112, 1074, 1004, 906, 822;MS: (EI, 70 eV) m/z (%)¼338 (M+, 1), 226 (M+�C5H10O,2), 156 (C11H8O+, 95), 155 (C11H7O+, 96), 128 (C10H8

+,27), 127 (C10H7

+, 100), 83 (C6H11+ , 17); HRMS: (EI, 70 eV,

C22H26O3) calcd: M¼338.188 g/mol, found: M¼338.188�0.005 g/mol; CH-analysis: (C22H26O3, M¼338.44) calcd:C, 78.07; H, 7.74, found: C, 77.49; H, 7.90.

4.1.2.15. (3RS,5RS,6RS)-3,5-Dicyclohexyl-6-(prop-1-en-2-yl)-1,2,4-trioxane (4f). 1H NMR: d 0.92–2.12 (m,22H, CH and CH2), 1.71 (s, 3H, CH3C]), 3.48 (d, 1H,J¼9.6 Hz, OCH), 4.54 (d, 1H, J¼9.5 Hz, OOCH), 4.95 (d,1H, J¼5.6 Hz, OCHOO), 5.05 (m, 2H, CH2]). 13C NMR:d 19.7 (q, CH3C]), 25.7 (t, CH2), 25.7 (t, CH2), 25.8 (t,CH2), 26.0 (t, CH2), 26.2 (t, CH2), 26.3 (t, CH2), 26.5 (t,CH2), 27.1 (t, CH2), 27.3 (t, CH2), 30.1 (t, CH2), 38.3 (d,CH), 40.6 (d, CH), 80.6 (d, OCH), 85.2 (d, OOCH), 107.1(d, OCHOO), 118.1 (t, CH2]C), 139.1 (s, C]CH2).

4.1.2.16. (3RS,5RS,6RS)-5-Allyl-3-(naphthalen-2-yl)-6-(prop-1-en-2-yl)-1,2,4-trioxane (3g). Following GP 2,a solution of 3-hydroperoxy-2-methylhepta-1,6-dien-4-ol(2g) (0.39 g, 2.47 mmol) and b-naphthaldehyde (388 mg,2.49 mmol) in CH2Cl2 was treated with a catalytic amountof BF3$Et2O (0.2 mL). Usual work-up and further purifica-tion of the crude product by preparative thick-layer chroma-tography (SiO2, EA/n-hex, 1:10, Rf¼0.69) afforded the pure1,2,4-trioxanes (30 mg, 0.10 mmol, 4%) as viscous colorlessoil, which crystallizes on standing, mp 55–57 �C. 1H NMR:d 1.82 (m, 3H, CH3C]), 2.47 (m, 2H, CH2), 4.06 (ddd,1H, J¼3.9, 7.2, 9.2 Hz, OCH), 4.64 (d, 1H, J¼9.2 Hz,OOCH), 5.15 (m, 4H, CH2]CH and CH2]C), 6.0 (m, 1H,CH]CH2), 6.37 (s, 1H, OCHOO), 7.45–8.0 (m, 7H, Harom);13C NMR: d 19.7 (q, CH3C]), 35.1 (t, CH2), 76.8 (d, OCH),87.1 (d, OOCH), 104.1 (d, OCHOO), 117.7 (t, CH2]CH),119.0 (t, CH2]C), 124.1 (d, CHarom), 126.2 (d, CHarom),126.7 (d, CHarom), 126.9 (d, CHarom), 127.7 (d, CHarom),128.2 (d, CHarom), 128.5 (d, CHarom), 131.8 (s, Cqarom),132.9 (s, Cqarom), 133.4 (d, CH]CH2), 134.0 (s, Cqarom),138.5 (s, C]CH2); MS: (EI, 70 eV) m/z (%)¼296 (M+, 7),156 (C11H8O+, 100), 155 (C11H7O+, 86), 127 (C10H7

+, 62);HRMS: (EI, 70 eV, C19H20O3) calcd: M¼296.141 g/mol,found: M¼296.141�0.005 g/mol; CH-analysis: (C19H20O3,M¼296.36) calcd: C, 77.00; H, 6.80, found: C, 76.85; H,6.71.

4.1.2.17. (3RS,5RS,6RS)-5-((RS)-But-3-en-2-yl)-3-(naphthalen-2-yl)-6-(prop-1-en-2-yl)-1,2,4-trioxane and(3RS,5RS,6RS)-5-((SR)-but-3-en-2-yl)-3-(naphthalen-2-yl)-6-(prop-1-en-2-yl)-1,2,4-trioxane (3h). Following GP2, a solution of 3-hydroperoxy-2,5-dimethylhepta-1,6-dien-4-ol (2h) (1.16 g, 6.74 mmol) and 2-naphthaldehyde(1.07 g, 6.86 mmol) in CH2Cl2 was treated with a catalyticamount of BF3$Et2O (0.2 mL). Usual work-up and further

10622 A. G. Griesbeck et al. / Tetrahedron 62 (2006) 10615–10622

purification of the crude product (1.62 g, 5.23 mmol, 77.5%)by preparative thick-layer chromatography (SiO2, EA/n-hex, 1:10, Rf¼0.69) afforded a diastereomeric mixtureof the pure 1,2,4-trioxanes 3h in a ratio 1:1 (0.31 g,1.0 mmol, 15%) as white solid. 1H NMR first diastereomer:d 1.30 (d, 3H, J¼7.0 Hz, CH3CH), 1.88 (t, 3H, J¼1.5 Hz,CH3C]), 2.55 (m, 1H, CHCH3), 4.02 (dd, 1H, J¼1.9,9.5 Hz, OCH), 4.83 (d, 1H, J¼9.5 Hz, OOCH), 5.20 (m,4H, CH2]CH and CH2]), 6.15 (m, 1H, CH]CH2), 6.40(s, 1H, OCHOO), 7.50–8.10 (m, 7H, Harom); 13C NMR firstdiastereomer: d 13.5 (q, CH3CH), 19.5 (q, CH3C]), 38.1 (d,CHCH3), 79.9 (d, OCH), 85.4 (d, OOCH), 103.9 (d,OCHOO), 114.3 (t, CH2]CH), 118.9 (t, CH2]C), 124.0(d, CHarom), 126.1 (d, CHarom), 126.6 (d, CHarom), 126.8(d, CHarom), 126.9 (d, CHarom), 127.6 (d, CHarom), 128.0 (d,CHarom), 131.9 (s, Cqarom), 132.7 (s, Cqarom), 133.9 (s,Cqarom), 138.5 (d, CH]CH2), 138.6 (s, C]CH2); 1HNMR additional signals of the other diastereomer: d 4.12(dd, 1H, J¼2.51, 9.6 Hz, OCH), 4.89 (d, 1H, J¼9.6 Hz,OOCH), 6.41 (s, 1H, OCHOO); 13C NMR other diastereo-mer: d 18.2 (q, CH3CH), 19.5 (q, CH3C]), 38.8 (d,CHCH3), 80.0 (d, OCH), 85.6 (d, OOCH), 104.0 (d,OCHOO), 116.1 (t, CH2]CH), 118.9 (t, CH2]C), 124.0(d, CHarom), 126.1 (d, CHarom), 126.6 (d, CHarom), 126.8(d, CHarom), 126.9 (d, CHarom), 127.6 (d, CHarom), 128.3 (d,CHarom), 131.9 (s, Cqarom), 132.7 (s, Cqarom), 133.9 (s,Cqarom), 138.4 (s, C]CH2), 140.8 (d, CH]CH2); IR:(CsI) n (cm�1)¼3078, 2978, 2923, 1653, 1647, 1605,1127, 1076, 999, 987, 904, 866, 818; MS: (EI, 70 eV) m/z(%)¼310 (M+, 2), 226 (M+�C5H8O, 1), 156 (C11H8O+,100), 155 (C11H7O+, 89), 128 (C10H8

+, 20), 127 (C10H7+,

68), 107 (C8H11+ , 20); HRMS: (EI, 70 eV, C20H22O3) calcd:

M¼310.157 g/mol, found: M¼310.157�0.005 g/mol; CH-analysis: (C20H22O3, M¼310.39) calcd: C, 77.39; H, 7.14,found: C, 77.28; H, 7.02.

Acknowledgements

This research was supported by the Deutsche Forschungsge-meinschaft. T.T.E. thanks the Egyptian government and theKurt-Alder foundation (University of Cologne) for a Ph.D.grant.

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